Known drug-drug interactions (DDIs) are responsible for 13 percent of adverse drug events and 4.8 percent of hospital admissions in older adults. Even these high figures may understate the true impact of DDIs because they include only the effects of known interactions. Many clinically important DDIs take years to discover. Given the widespread and growing use of multiple medications by persons with diabetes, there is tremendous potential for DDIs to occur in this population. Of the ten most commonly used second-line antidiabetic agents, five are insulin secretagogues, which, based on known metabolic pathways, may interact with many commonly- prescribed medications. DDIs involving insulin secretagogues can cause serious hypoglycemia, which can be immediately life-threatening and have cause long-term consequences. The broad objective of this project is to produce clinically-actionable knowledge about which drugs interact with insulin secretagogues to cause serious hypoglycemia, as well as the time-course of such interactions and the subgroups most susceptible to these DDIs. We will achieve this objective by taking a translational science approach to DDIs in which we 1) perform high-throughput simulation of potential DDIs based on pharmacologic knowledge; 2) perform high-throughput screening of healthcare data; and then 3) confirm (or refute) and elucidate selected high-probability DDIs in an independent population by conducting in-depth pharmacoepidemiologic studies. This project will produce clinically-actionable knowledge about which drugs interact with secretagogues to cause severe hypoglycemia, and generalizable biological knowledge about the drugs and pathways involved in these interactions.